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Abstract：
Introduction Recent publications have described drug reaction with eosinophilia and systemic symptoms (DRESS) with topiramate. Topiramate has been associated with other severe cutaneous adverse reactions, including Stevens-Johnson syndrome, but a relationship to DRESS has not been established. To determine if there is a causal association between topiramate and DRESS, we conducted a comprehensive review of the data in the Janssen Research & Development Global Safety Database (GSD), signaling databases, and the literature. Methods The primary data were post-marketing reports of DRESS in the Janssen topiramate GSD (cumulative through 1 July 2022), representing >14,000,000 patient-years (PY) exposure. Cases were reviewed, assigned a Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) score, and assessed for overall contribution of topiramate to DRESS based on temporality, concomitant medications, dechallenge/rechallenge, and baseline patient factors. Statistical disproportionality was evaluated in European Medicines Agency\'s EudraVigilance (EV) safety database and the United States Food and Drug Administration Adverse Event Reporting System (FAERS). For EV, the overall disproportionality threshold was the lower limit of the 95% confidence interval (CI) for the reporting odds ratio (ROR025) >1 and N ≥5. The overall threshold for FAERS was the Empirical Bayesian Geometric Mean (EBGM) ≥2, lower bound of the 90% CI (EB05) of >1, and N ≥3. To account for the role of concomitant drugs, Empirical Bayes regression-adjusted arithmetic mean (ERAM) scores were calculated, with a threshold ≥2, a lower bound of the 90% CI (ER05) of >1, and N ≥3. An integrated search of major biomedical literature was performed for reports of topiramate and DRESS. Results There were 17 reports of DRESS in the GSD (reporting rate 0.12/100,000 PY). RegiSCAR scores ranged from -3 to 7 (average -0.4). No cases met full diagnostic criteria and were highly confounded by the presence of other suspect drugs. Disproportionality scores exceeded thresholds for statistical significance in FAERS (N=72, EBGM=2.06, EB05=1.69), but not in EV (N=33, ROR025=0.79). When accounting for co-administered drugs, ERAM was statistically significant for carbamazepine (4.53), lamotrigine (ERAM=6.54), phenytoin (ERAM=2.91), and zonisamide (ERAM=2.25) exceeding disproportionality thresholds, but the score of topiramate was no longer significant (0.25). Conclusion A comprehensive review of all available evidence does not support a causal association between topiramate and DRESS.
摘要：
介绍最近的出版物已经描述了托吡酯与嗜酸性粒细胞增多和全身症状(DRESS)的药物反应。托吡酯与其他严重的皮肤不良反应有关，包括史蒂文斯-约翰逊综合征,但与DRESS的关系尚未建立。为了确定托吡酯和DRESS之间是否存在因果关系，我们对扬森研发全球安全数据库(GSD)中的数据进行了全面审查，信令数据库，和文学。方法主要数据是Janssen托吡酯GSD中DRESS的上市后报告（累积至2022年7月1日），代表>14,000,000患者年(PY)暴露。案件进行了审查，分配了严重皮肤不良反应（RegiSCAR）评分，并根据时间性评估托吡酯对DRESS的总体贡献，合并用药,解除挑战/重新挑战，和基线患者因素。在欧洲药品管理局的EudraVigilance（EV）安全数据库和美国食品和药物管理局不良事件报告系统（FAERS）中评估了统计不相称性。对于EV，总体不成比例阈值是报告比值比(ROR025)>1和N≥5的95%置信区间(CI)下限.FAERS的总体阈值为经验贝叶斯几何平均值（EBGM）≥2，90%CI（EB05）的下限>1，N≥3。为了解释伴随药物的作用，计算了经验贝叶斯回归调整后的算术平均值(ERAM)分数，阈值≥2，90%CI(ER05)的下限>1，N≥3。对托吡酯和DRESS的报道进行了主要生物医学文献的综合检索。结果GSD中有17例DRESS报告（报告率0.12/100,000PY）。RegiSCAR评分范围为-3至7(平均-0.4)。没有病例符合完整的诊断标准，并且由于其他可疑药物的存在而高度混淆。在FAERS中，不相称性得分超过了统计学意义的阈值（N=72，EBGM=2.06，EB05=1.69），但不在EV中(N=33，ROR025=0.79)。在考虑共同用药时，卡马西平的ERAM具有统计学意义（4.53），拉莫三嗪（ERAM=6.54），苯妥英（ERAM=2.91），和唑尼沙胺（ERAM=2.25）超过不成比例阈值，但托吡酯评分不再显著(0.25).结论对所有现有证据的综合评价不支持托吡酯和DRESS之间的因果关系。
